Although ˜4% of the mammalian genome encodes genes expressed in male germ cells during spermatogenesis, contraceptive drugs for men have remained elusive. To date, the only drugs in clinical trials are testosterone analogs that alter endogenous androgen production. This lack of contraceptive alternatives for men is partially responsible for the high rate of unplanned pregnancies, especially in teenagers, and the associated maternal mortality and ethical, social, and financial costs associated with abortions and deliveries to single mothers. To approach this dearth of contraceptive alternatives for men, it is desirable to develop small molecules that could target spermatogenic-specific proteins that have been shown to be essential for both spermatogenesis and fertility in mammals. One such contraceptive target is the bromodomain testis-specific protein, BRDT.
BRDT is a tissue-restricted, chromatin remodeling protein expressed in pachytene spermatocytes, diplotene spermatocytes, and round spermatids. During post-meiotic maturation, BRDT localizes to the nucleus and reorganizes hyperacetylated histones through twin acetyl-lysine recognition modules, or bromodomains. The essential role of BRDT in spermatogenesis is mediated by the first bromodomain (BRDT(1)), which binds the tetra-acetylated amino-terminal tail of histone 4 (H4Kac4) with moderate potency (20 μM). Structural studies of murine BRDT have demonstrated that BRDT(1) binds a diacetylated histone 4 peptide (H4K5ac8ac) in part through a conserved asparagine, akin to seminal studies of other bromodomain co-activator proteins. Genetic studies of BRDT have demonstrated that selective deletion of the BRDT(1)-encoding region is sufficient to confer sterility in homozygous male mice, and a recently published genome-wide association study of idiopathic male infertility identified single nucleotide polymorphisms of BRDT as significantly associated with oligozoospermia or azoospermia in European men. These insights establish a compelling rationale to target BRDT for a contraceptive effect.